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In this prospective longitudinal multiple-cohort study, we investigated mental health outcomes in patients with traumatic brain injury (TBI) or Orthotrauma (fracture excluding head/neck) using data from six University of California civilian healthcare settings between 2013 and 2022. Trauma cohorts were propensity matched 1:1 by age, race and ethnicity, sex, site, insurance coverage, area deprivation index, and number of visits within the year preceding injury diagnosis in the health record (index), then propensity matched to unexposed individuals. International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes identified patients and study mental health outcomes (depression, anxiety, post-traumatic stress or PTSD, suicidality, bipolar disorder, schizophrenia). Cox proportional hazard models generated hazard ratios (HR) from 1 year pre- to 7 years post-index for 3 groups: TBI vs unexposed, Orthotrauma vs unexposed, and TBI vs Orthotrauma. Analyses included patients with pre-index mental health outcomes and were adjusted for documented suicide attempt. Age and sex stratifications were explored. Results included 174,384 patients (99,356 female [57.0%]; 10,584 Black [6.1%]), including 43,596 each in TBI and Orthotrauma cohorts and 87,192 unexposed (all median [IQR] age, 57.0 [42.0-70.0] years). Compared to Orthotrauma, TBI affected post-index HRs most strongly for PTSD (HR range 1.75-2.59 through Year 6, pre-index 1.74-1.84) and suicidality (HR range 2.34-6.17 through Year 7, pre-index 1.51-1.95) with particularly elevated suicidality risk within 6-12 months of index. Mental health diagnoses served as precursors to and consequences of TBI. Patients with traumatic injuries should be screened and treated for mental health conditions. Etiologic studies are urgently needed.